Tourette syndrome (TS) is a common, hereditary, neurobehavioral disorder characterized by motor and vocal tics. In addition to the tics the applicant has shown that TS is associated with a wide range of other behavioral disorders in both the patients and their relatives. These include attention deficit disorder (ADD) with or without hyperactivity, autism (a trait of three sets of symptoms: (1) a profound failure to develop social relationships; (2) defective speech and language; and (3) ritualistic or compulsive behavior), obsessive-compulsive behaviors, unipolar or bipolar affective disorder, phobias, panic attacks, premenstrual syndrome (PMS), generalized anxiety disorder, pervasive developmental disorder, dyslexia, learning disabilities, dysgraphia, mental retardation, specific math disabilities, specific reading disabilities, specific spelling disabilities, borderline personality disorder, migraine headaches, exhibitionism, stuttering, delayed speech, schizophreniform disorder, schizoid disorder, drug or alcohol addiction or abuse, bulimia, compulsive eating with obesity, physical or sexual abuse of spouse or children, somatiform disorders including spastic colon, (irritable bowel syndrome), chronic fatigue syndrome, sleep disturbances, sleep apnea, sudden infant death syndrome (SIDS), narcolepsy, insomnia, short temper, and temper tantrums.
Hereinafter these abnormalities are collectively referenced as "TS related disorders" or "TS spectrum of disorders."
The applicant has proposed that the symptoms of TS, and TS related disorders, fit a model in which the frontal lobe and limbic system in the brain are disinhibited by a relative deficiency in brain serotonin and tryptophan and that these chemical deficiencies are due to genetic defects in the two major genes that cause the breakdown of tryptophan--tryptophan 2,3-dioxygenase and indoleamine 2,3- dioxygenase and that tests for mutations in these genes will be an extremely useful adjunct in the diagnosis and treatment of TS and TS associated behaviors.
Tryptophan 2,3-dioxygenase (tryptophan oxygenase, tryptophan pyrrolase) and indoleamine 2,3 dioxygenase, are similar but separate enzymes. See Gal, E. M. and Sherman, A. D., "DL-kynurenine: its synthesis and possible regulatory function in brain", Neurochem.Res. 5:223-239 (1980).
Table 1 depicts several apparent similarities and differences between the functions of these enzymes. See Hayaishi, O., "Properties and function of indoleamine 2,3-dioxygenase," Biochem. 79:13p-21p (1976); Gal, E. M., "Cerebral tryptophan-2,3-dioxygenase (pyrrolase) and its induction in rat brain" Neurochem. 22:861-863 (1974); and Gal, E. M. and Sherman, A. D. "DL-kynurenine: its synthesis and possible regulatory function in brain", Neurochem. Res. 5:223-239 (1980).
TABLE 1 ______________________________________ Tryptophan Indoleamine 2,3-dioxygenase 2,3-dioxygenase ______________________________________ Similarities Substrate L-tryptophan L-tryptophan Oxygen Oxygen Product N-formyl N-formyl L-kynurenine L-kynurenine Cofactor heme heme Induced by: tryptophan tryptophan Differences Location liver, red blood intestine, brain cells, brain other organs Type of oxygen used O.sub.2 O--O.sup.- Other substrates none D-tryptophan 5-hydroxy- tryptophan serotonin melantoin Inducible by steroids yes no Inducible by interferon no yes ______________________________________
The nucleotide sequence of human indoleamine 2,3-dioxygenase has been published. See Gupta S. L. and Dal, W. "Molecular cloning, sequencing and expression of human interferon-gamma-inducible indoleamine 2.3-dioxygenase cDNA" Biochem. Biophys. Res. Comm. 168:1-8 (1990). Comparison of this published sequence of indoleamine 2,3-dioxygenase with the sequence of tryptophan dioxygenase disclosed (See FIG. 8) indicates that the two enzymes are produced by different genes. Accordingly, the predominantly liver enzyme, tryptophan 2,3-dioxygenase is referred to herein as TD02, the brain-intestine enzyme, indoleamine 2,3-dioxygenase is referred to as ID02. Collectively, these two enzymes are labelled TD02-ID02 which means TD02 and/or ID02.
If TD02-ID02 activity were present only in the liver-intestine, then the level of tryptophan in the brain would be almost completely dependent on the blood level of tryptophan and of the other large amino acids that compete for its transport across the blood brain barrier. However, as FIG. 1 shows, TOD2-ID02 activity is present in the brain where it is effective to siphon off some of the tryptophan after entry into the brain and before it is converted to serotonin. In rats, under normal conditions 70% of the brain tryptophan is converted to serotonin and 30% to brain kynurenine. See Gal, E. M. and Sherman, A. D., "DL-kynurenine: its synthesis and possible regulatory function in brain", Neurochem. Res. 5:223-239 (1980).
Thus, even a moderate increase in brain TD02-ID02 activity could markedly change this ratio and lower the level of brain serotonin. Significant changes in the breakdown of tryptophan in the brain may thus occur concurrently with only moderate changes in the blood tryptophan and serotonin.
In humans, serotonin and tryptophan levels are apparently interdependent, serotonin level abnormalities being a consequence of tryptophan level abnormalities. As FIG. 2 shows, peripheral tryptophan can take two major metabolic pathways, i.e., 90% conversion to kynurenine and 10% conversion to serotonin. TD02-ID02 activity is the rate limiting step in the degradation of tryptophan to kynurenine.
Mutations of the TD02-ID02 genes are implicated in TS and TS associated behaviors and changes in the level of these enzymes would be expected to significantly affect serotonin production. While it is anticipated that TS and most of the TS related disorders will be due to mutations that increase the level of TD02-ID02, since some TS or autistic children have either too low or too high levels of serotonin, the basic defect is both may be a "dysregulation" of serotonin usually a result of too much, but occasionally too little, TD02-ID02.
FIG. 3 indicates that genetic defects in TD02-ID02 that may occur in TS, and TS related disorders, and in autism. The applicant's studies show that children with autism often develop full blown symptoms of TS as they grow older. (See Comings, D. E. and Comings, B. G., "Clinical and genetic relationships between autism-PDD and Tourette syndrome: A study of 19 cases." Amer. J. Med. Genetics 39:180-191 (1991). Thus many cases of autism may in fact be due to the same genetic defect that causes TS.